The invention relates to the combination of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoro-methoxybenzamide, its pharmacologically tolerable salts or its N-oxide with known active compounds from the class of PDE3 inhibitors for therapeutic purposes.
The substances used in the combination according to the invention are, on the one hand, N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy4-difluoromethoxybenzamide, Its pharmacologically tolerable salts or its N-oxide [xe2x95x90N-(3,5-dichloro-1-oxypyrid-4-yl)3-cyclopropylmethoxy-4-difluoromethoxybenzamide], all of them PDE4 inhibitors, which are described in the international application WO 95/01338 and, on the other hand, known active compounds from the class of PDE3 inhibitors.
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are ubiquitous intracellular second messengers which are involved in many biological processes which are induced by a huge variety of extracellular stimulants. The inactivation (metabolization) of cAMP and cGMP is effected by enzymes of the cyclic nucleotide phosphodiesterase (PDE) type. At least nine different families of PDE isoenzymes have meanwhile been identified (PDE1 to PDE9).
The PDE3 and PDE4 isoenzyme families caused particular interest; a definitive role in the inactivation of cAMP is ascribed to both. Inhibitors of these isoenzymes exhibit actions on the airways, on the peripheral blood pressure, on the central nervous system (e.g. increase in respiratory rates) and anti-inflammatory actions.
The effect on the airways is essentially ascribed to the inhibition of PDE3 and, to a minor extent, also to the inhibition of PDE4. The effects on the blood pressure is regarded as mediated by PDE3, while the anti-inflammatory action and the action on the central nervous system are assigned to the inhibition of PDE4.
The combined use of the PDE4 inhibitor N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy4-difluoromethoxybenzamide, its pharmacologically tolerable salts or Its N-oxide with a PDE3 inhibitor in the sense according to the invention has still not been described in the prior art.
The invention relates to the combined use of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, its pharmacologically tolerable salts or its N-oxide with a PDE3 inhibitor in the treatment of disease conditions which are based on acute or chronic obstruction of vessels and/or bronchi and/or on acute or chronic inflammation.
The preparation of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, its pharmacologically tolerable salts and its N-oxide and the use of these compounds as phosphodiesterase (PDE) 4 inhibitors is described in the international application WO 95/01338.
Pharmacologically tolerable salts of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy4-difluoromethoxybenzamide which may be mentioned are, for example, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparationxe2x80x94depending on whether it is a mono- or polybasic acid and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.